Apo2L/TRAIL and its death and decoy receptors

Leblanc, Heidi; Ashkenazi, Avi

doi:10.1038/sj.cdd.4401187

Cited by 798 publications

(738 citation statements)

References 91 publications

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“…EtOH treatment of untransfected Huh7.5 cells did not cause cell death, but after FOXO3 overexpression, EtOH caused a significant increase in TUNEL positivity, LDH release and caspase 3/7 activity (Figures 1e-g). DR4 and DR5, the TRAIL receptor antagonists, 24 significantly blocked FOXO3/EtOH-induced increases of LDH release and caspase 3/7 activity (Figures 1f and g), demonstrating that FOXO3/EtOH-induced cell death was TRAIL dependent. These data indicate that EtOH reprograms FOXO3, enhancing its activation of pro-apoptotic target genes that contribute to TRAIL-dependent apoptosis.…”

Section: Resultsmentioning

confidence: 85%

Serine 574 phosphorylation alters transcriptional programming of FOXO3 by selectively enhancing apoptotic gene expression

Zhao

Tikhanovich

et al. 2015

Cell Death Differ

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Forkhead box O3 (FOXO3) is a multispecific transcription factor that is responsible for multiple and conflicting transcriptional programs such as cell survival and apoptosis. The protein is heavily post-translationally modified and there is considerable evidence that post-transcriptional modifications (PTMs) regulate protein stability and nuclear-cytosolic translocation. Much less is known about how FOXO3 PTMs determine the specificity of its transcriptional program. In this study we demonstrate that exposure of hepatocytes to ethanol or exposure of macrophages to lipopolysaccharide (LPS) induces the c-Jun N-terminal kinase (JNK)-dependent phosphorylation of FOXO3 at serine-574. Chromatin immunoprecipitation (ChIP), mRNA and protein measurements demonstrate that p-574-FOXO3 selectively binds to promoters of pro-apoptotic genes but not to other well-described FOXO3 targets. Both unphosphorylated and p-574-FOXO3 bound to the B-cell lymphoma 2 (Bcl-2) promoter, but the unphosphorylated form was a transcriptional activator, whereas p-574-FOXO3 was a transcriptional repressor. The combination of increased TRAIL (TNF-related apoptosis-inducing ligand) and decreased Bcl-2 was both necessary and sufficient to induce apoptosis. LPS treatment of a human monocyte cell line (THP-1) induced FOXO3 S-574 phosphorylation and apoptosis. LPS-induced apoptosis was prevented by knockdown of FOXO3. It was restored by overexpressing wild-type FOXO3 but not by overexpressing a nonphosphorylatable S-574A FOXO3. Expression of an S-574D phosphomimetic form of FOXO3 induced apoptosis even in the absence of LPS. A similar result was obtained with mouse peritoneal macrophages where LPS treatment increased TRAIL, decreased Bcl-2 and induced apoptosis in wild-type but not FOXO3 −/− cells. This work thus demonstrates that S-574 phosphorylation generates a specifically apoptotic form of FOXO3 with decreased transcriptional activity for other well-described FOXO3 functions. Forkhead box O3 (FOXO3) is a multispecific transcription factor that serves as a longevity factor 1,2 and tumor suppressor and is critically involved in multiple seemingly independent biological process including cell-cycle arrest, 3 DNA repair, 4 antioxidant and stress responses, 5 apoptosis, 6 autophagy, glucose metabolism and aging. 7 Its many transcriptional programs are frequently in opposition to each other as it induces apoptosis, yet it is also critical for cell survival and longevity. Although there is considerable information regarding the mechanisms that regulate the nuclear/cytosolic distribution and protein stability of FOXO3, the control mechanisms that regulate transcriptional specificity are poorly understood.FOXO3 function is tightly regulated by multiple posttranslational modifications (PTMs) including phosphorylation, acetylation, ubiquitination and arginine and lysine methylation. Specific PTMs regulate the partitioning of FOXO3 between the cytosol and the nucleus 8-15 and its stability and degradation, 16 but the links between specific PTMs and FOXO3 tran...

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Section: Resultsmentioning

confidence: 85%

Serine 574 phosphorylation alters transcriptional programming of FOXO3 by selectively enhancing apoptotic gene expression

Zhao

Tikhanovich

et al. 2015

Cell Death Differ

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“…TRAIL mediates apoptosis through two death receptors, TRAIL-receptor 1 (TRAIL-R1, DR4, TNFRSF10A) and TRAIL-receptor 2 (TRAIL-R2, DR5, TNFRSF10B). While additional receptor proteins that bind TRAIL exist (TRAIL-R3/DcR1, TRAIL-R4/DcR2, Osteoprotegerin/ OPG), these receptors lack functional death domains and, as such, do not initiate apoptosis (LeBlanc and Ashkenazi, 2003;MacFarlane, 2003).…”

mentioning

confidence: 99%

HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo

et al. 2005

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Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a variety of tumour cells through activation of TRAIL-R1 and TRAIL-R2 death signalling receptors. Here, we describe the characterisation and activity of HGS-ETR1, the first fully human, agonistic TRAIL-R1 mAb that is being developed as an antitumour therapeutic agent. HGS-ETR1 showed specific binding to TRAIL-R1 receptor. HGS-ETR1 reduced the viability of multiple types of tumour cells in vitro, and induced activation of caspase 8, Bid, caspase 9, caspase 3, and cleavage of PARP, indicating activation of TRAIL-R1 alone was sufficient to induce both extrinsic and intrinsic apoptotic pathways. Treatment of cell lines in vitro with HGS-ETR1 enhanced the cytotoxicity of chemotherapeutic agents (camptothecin, cisplatin, carboplatin, or 5-fluorouracil) even in tumour cell lines that were not sensitive to HGS-ETR1 alone. In vivo administration of HGS-ETR1 resulted in rapid tumour regression or repression of tumour growth in pre-established colon, non-smallcell lung, and renal tumours in xenograft models. Combination of HGS-ETR1 with chemotherapeutic agents (topotecan, 5-fluorouracil, and irinotecan) in three independent colon cancer xenograft models resulted in an enhanced antitumour efficacy compared to either agent alone. Pharmacokinetic studies in the mouse following intravenous injection showed that HGS-ETR1 serum concentrations were biphasic with a terminal half-life of 6.9 -8.7 days and a steady-state volume of distribution of approximately 60 ml kg À1 . Clearance was 3.6 -5.7 ml À1 day À1 kg À1 . These data suggest that HGS-ETR1 is a specific and potent antitumour agent with favourable pharmacokinetic characteristics and the potential to provide therapeutic benefit for a broad range of human malignancies.

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“…Besides DR4 (TRAIL‐R1) and DR5 (TRAIL‐R2), other receptors also bind TRAIL and appear to act as ‘decoys’: DcR1 (TRAIL‐R3), DcR2 (TRAIL‐R4), and OPG (LeBlanc & Ashkenazi, 2003). DcR2 has a truncated nonfunctional death domain, and DcR1 does not contain transmembrane and death domains.…”

Section: Discussionmentioning

confidence: 99%

Activation of TRAIL‐DR5 pathway promotes sensorineural degeneration in the inner ear

et al. 2016

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SummaryTumor necrosis factor (TNF) family cytokines are important mediators of inflammation. Elevated levels of serum TNF‐α are associated with human sensorineural hearing loss via poorly understood mechanisms. We demonstrate, for the first time, expression of TNF‐related apoptosis‐inducing ligand (TRAIL) and its signaling death receptor 5 (DR5) in the murine inner ear and show that exogenous TRAIL can trigger hair cell and neuronal degeneration, which can be partly prevented with DR5‐blocking antibodies.

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Apo2L/TRAIL and its death and decoy receptors

Cited by 798 publications

References 91 publications

Serine 574 phosphorylation alters transcriptional programming of FOXO3 by selectively enhancing apoptotic gene expression

Serine 574 phosphorylation alters transcriptional programming of FOXO3 by selectively enhancing apoptotic gene expression

HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo

Activation of TRAIL‐DR5 pathway promotes sensorineural degeneration in the inner ear

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